We have recently developed a novel model of PD based on chronic, systemic administration of the pesticide, rotenone, to rats. This model faithfully reproduces the behavioral, anatomical, biochemical and neuropathological features of PD. Now, in an effort to delineate the mechanisms by which rotenone causes the formation of Lewy body-like inclusions and induces dopamine cell death, we propose to develop and use new in vitro and in vivo models combined with genetically modified animals. In this way, we will examine the interaction of environmental exposures and genetic factors that confer susceptibility or resistance to neurodegeneration in PD. Aim 1 : To develop a mouse model of rotenone-induced parkinsonism. (a) To apply the new model to study the interaction of rotenone with pathogenic alpha-synuclein and parkin mutations in transgenic mice. (b) To apply the new model to study the effects of endogenous antioxidant and chaperone systems on rotenone-induced parkinsonism using genetically modified mice. (c) To study whether VMAT2 expression alters rotenoneinduced parkinsonism. Aim 2: To develop an organotypic brain slice model of rotenone-induced, selective dopaminergic degeneration. (a) To use the new model to examine the mechanisms by which rotenone causes selective neuronal degeneration in normal mice. (b) To assess the role of dopamine in rotenone-induced dopaminergic toxicity. (c) To use slices from genetically modified mice to examine the roles of specific genes, including alpha- synuclein, parkin and VMAT2, in selective dopaminergic degeneration. Aim 3: To screen several commonly used pesticides, which are known to potently inhibit complex I, for their ability to induce parkinsonism in normal mice. Aim 4: To screen potential neuroprotective compounds in the organotypic slice and in vivo models of rotenone-induced parkinsonism.